Polymorphs of sorafenib acid addition salts

ABSTRACT

The present invention provides amorphous and crystalline forms of acid addition salts of sorafenib, pharmaceutical compositions comprising them and their use for the treatment of cancer. The present invention also provides processes for the preparation of acid addition salts of sorafenib.

FIELD OF THE INVENTION

The present invention provides amorphous and crystalline forms ofsorafenib acid addition salts, process for their preparation,pharmaceutical compositions comprising them and their use for thetreatment of cancer. The present invention also provides a process forthe preparation of sorafenib acid addition salts.

BACKGROUND OF THE INVENTION

Sorafenib is an inhibitor of the enzyme Raf kinase known from WO00/42012. It is chemically4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N²-methylpyridine-2-carboxamide having the structure asrepresented by Formula I.

Sorafenib is marketed in the United States as its tosylate salt ofFormula II under the brand name Nexavar®.

Several acid addition salts of sorafenib are disclosed in WO 00/42012.

Processes for the preparation of sorafenib tosylate are disclosed in WO2006/034796, WO 2006/034797, WO 2009/034308, WO 2009/054004, WO2009/106825 and WO 2009/092070, which are incorporated herein byreference. Besides sorafenib tosylate, no other salt of sorafenib hasbeen prepared in the literature.

SUMMARY OF THE INVENTION

The present invention provides amorphous and crystalline forms ofsorafenib acid addition salts, a process for their preparation,pharmaceutical compositions comprising them and their use for thetreatment of cancer. The present invention also provides processes forthe preparation of sorafenib acid addition salts.

A first aspect of the present invention provides crystalline form ofsorafenib hydrochloride of Formula III.

A second aspect of the present invention provides crystalline form ofsorafenib hydrobromide of Formula IV.

A third aspect of the present invention provides crystalline form ofsorafenib methane sulphonate of Formula V.

A fourth aspect of the present invention provides amorphous form ofsorafenib sulphate of Formula VI.

A fifth aspect of the present invention provides process for thepreparation of acid addition salts of sorafenib of Formula VII

wherein HX is an acid addition salt as defined herein.comprising contacting sorafenib free base of Formula I

with an acid of Formula HX

A sixth aspect of the present invention provides use of sorafenib acidaddition salts for the preparation of high purity sorafenib base.

A seventh aspect of the present invention provides use of a sorafenibacid addition salt as an intermediate for the preparation of sorafenibtosylate.

An eighth aspect of the present invention provides pharmaceuticalcompositions comprising sorafenib acid addition salts of Formula VII andone or more pharmaceutically acceptable carriers, diluents orexcipients.

A ninth aspect of the present invention provides use of sorafenib acidaddition salts of Formula VII for the treatment of cancer.

A tenth aspect of the present invention provides pharmaceuticalcomposition comprising sorafenib acid addition salts selected fromcrystalline sorafenib hydrochloride of Formula III, crystallinesorafenib hydrobromide of Formula IV, crystalline sorafenib methanesulphonate of Formula V, or amorphous sorafenib sulphate of Formula VI,and one or more pharmaceutically acceptable carriers, diluents orexcipients.

An eleventh aspect of the present invention provides use of sorafenibacid addition salts selected from crystalline sorafenib hydrochloride ofFormula III, crystalline sorafenib hydrobromide of Formula IV,crystalline sorafenib methane sulphonate of Formula V, or amorphoussorafenib sulphate of Formula VI for the treatment of cancer.

The present invention may involve one or more of the followingembodiments.

In one embodiment, crystalline sorafenib hydrochloride of Formula IIImay be characterized by X-ray diffraction (XRD) peaks having d-spacingvalues at 3.69, 3.63, 3.42, 3.39 and 3.05 Å. It may be furthercharacterized by XRD peaks having d-spacing values at 6.40, 4.22, 4.06and 3.60 Å. It may also be characterized by a Differential ScanningThermogram (DSC) having endotherms at about 68.33° C., 115.21° C. and152.74° C. Crystalline sorafenib hydrochloride of Formula III may alsobe characterized by XRD spectrum, DSC thermogram, ThermogravimetricAnalysis (TGA) and (Infra-Red) IR spectra as depicted in FIGS. 1, 2, 3and 4, respectively. Table 1 provides the 2θ, d-spacing values andrelative intensity of XRD peaks of sorafenib hydrochloride.

In another embodiment, crystalline sorafenib hydrobromide may becharacterized by XRD peaks having d-spacing values at 4.74, 4.66, 3.67,3.61 and 3.39 Å. It may be further characterized by XRD peaks havingd-spacing values at 5.28, 4.17, 3.73, 3.72 and 3.45 Å. It may also becharacterized by a DSC thermogram having endotherm at about 262.27° C.Crystalline sorafenib hydrobromide of Formula IV may also becharacterized by XRD spectrum, DSC thermogram, TGA and IR spectra asdepicted in FIGS. 5, 6, 7 and 8, respectively. Table 2 provides the 2θ,d-spacing values and relative intensity of XRD peaks of sorafenibhydrobromide.

In another embodiment, crystalline sorafenib methane sulphonate ofFormula V may be characterized by XRD peaks having d-spacing values at5.41, 5.20, 4.14, 3.68 and 3.58 Å. It may be further characterized byXRD peaks having d-spacing values at 10.80, 5.85, 5.20, 4.58 and 4.41 Å.It may also be characterized by a DSC thermogram having endotherm atabout 205.07° C. Crystalline sorafenib methane sulphonate of Formula Vmay also be characterized by XRD spectrum, DSC thermogram, TGA and IRspectra as depicted in FIGS. 9, 10, 11 and 12, respectively. Table 3provides the 2θ, d-spacing values and relative intensity of XRD peaks ofsorafenib methane sulphonate.

In another embodiment, amorphous sorafenib sulphate of Formula VI may becharacterized by XRD spectrum, DSC thermogram, TGA and IR spectrum asdepicted in FIGS. 13, 14, 15 and 16, respectively.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: XRD pattern of crystalline sorafenib hydrochloride.

FIG. 2: DSC thermogram of crystalline sorafenib hydrochloride.

FIG. 3: TGA curve of crystalline sorafenib hydrochloride.

FIG. 4: IR spectrum of crystalline sorafenib hydrochloride.

FIG. 5: XRD pattern of crystalline sorafenib hydrobromide.

FIG. 6: DSC thermogram of crystalline sorafenib hydrobromide.

FIG. 7: TGA curve of crystalline sorafenib hydrobromide.

FIG. 8: IR spectrum of crystalline sorafenib hydrobromide.

FIG. 9: XRD pattern of crystalline sorafenib methanesulphonate.

FIG. 10: DSC thermogram of crystalline sorafenib methanesulphonate.

FIG. 11: TGA curve of crystalline sorafenib methanesulphonate.

FIG. 12: IR spectrum of crystalline sorafenib methanesulphonate.

FIG. 13: XRD pattern of amorphous sorafenib sulphate.

FIG. 14: DSC thermogram of amorphous sorafenib sulphate.

FIG. 15: TGA curve of amorphous sorafenib sulphate.

FIG. 16: IR spectrum of amorphous sorafenib sulphate.

DETAILED DESCRIPTION OF THE INVENTION

Crystalline sorafenib hydrochloride of Formula III may be characterizedby XRD peaks at about 24.10±0.2° 2θ (d-spacing at 3.69 Å), 24.46±0.2° 2θ(3.63 Å), 26.00±0.2° 2θ (3.42 Å), 26.24±0.2° 2θ (3.39 Å) and 29.20±0.2°2θ (3.05 Å). It may be further characterized by XRD peaks at about 13.82(6.40 Å), 21.00 (4.22 Å), 21.85 (4.06 Å) and 24.71 (3.60 Å)±0.2 degrees2θ. Crystalline sorafenib hydrochloride of Formula III may also becharacterized by a DSC thermogram having endotherms at about 68.33° C.,115.21° C. and 152.74° C. Crystalline sorafenib hydrochloride of FormulaIII may also be characterized by XRD spectrum, DSC thermogram, TGA andIR spectrum as depicted in FIGS. 1, 2, 3 and 4, respectively.

Crystalline sorafenib hydrobromide of Formula IV may be characterized bypeaks in the powder X-ray diffraction pattern at about 18.69±0.2° 2θ(d-spacing at 4.74 Å), 19.03±0.2° 2θ (4.66 Å), 24.24±0.2° 2θ (3.67 Å),24.62±0.2° 2θ (3.61 Å) and 26.26±0.2° 2θ (3.39 Å). It may be furthercharacterized by X-ray diffraction peaks at 16.78±0.2° 2θ (5.28 Å),21.28±0.2° 2θ (4.17 Å), 23.77±0.2° 2θ (3.73 Å), 23.87±0.2° 2θ (3.72 Å)and 25.79±0.2° 2θ (3.45 Å). Crystalline sorafenib hydrobromide ofFormula IV may also be characterized by a DSC thermogram havingendotherm at about 262.27° C. Crystalline sorafenib hydrobromide ofFormula IV may also be characterized by XRD spectrum, DSC thermogram,TGA and IR spectrum as depicted in FIGS. 5, 6, 7 and 8, respectively.

Crystalline sorafenib methane sulphonate of Formula V may becharacterized by peaks in the powder X-ray diffraction pattern at about16.37±0.2° 2θ (5.41 Å), 17.01±0.2° 2θ (5.20 Å), 21.41±0.2° 2θ (4.14 Å),24.13±0.2° 2θ (3.68 Å) and 24.80±0.2° 2θ (3.58 Å). It may be furthercharacterized by X-ray diffraction peaks at 8.18±0.2° 2θ (10.80 Å),15.12±0.2° 2θ (5.85 Å), 17.01±0.2° 2θ (5.20 Å), 19.34±0.2° 2θ (4.58 Å)and 20.09±0.2° 2θ (4.41 Å). Crystalline sorafenib methane sulphonate ofFormula V may also be characterized by DSC thermogram having endothermat about 205.07° C. Crystalline sorafenib methane sulphonate of FormulaV may also be characterized by XRD spectrum, DSC thermogram, TGA and IRspectrum as depicted in FIGS. 9, 10, 11 and 12, respectively.

Amorphous sorafenib sulphate of Formula VI may be characterized by XRDspectrum, DSC thermogram, TGA and IR spectrum as depicted in FIGS. 13,14, 15 and 16, respectively.

Sorafenib free base to be used for the preparation of acid additionsalts of the present invention may be obtained by any of the methodsknown in the literature such as those described in PCT publications WO00/42012, WO 2006/034796, WO 2006/034797, WO 2009/034308, WO2009/054004, WO 2009/106825 and WO 2009/092070, which are incorporatedherein by reference.

In general, sorafenib freebase may be prepared by the reaction of4-(2-(N-methylcarbamoyl)-4-pyridyloxy) aniline with4-chloro-3-(trifluoromethyl) phenyl isocyanate. The starting sorafenibfreebase may be obtained as a solution directly from a reaction in whichsorafenib is formed and used as such without isolation.

The sorafenib acid addition salts may be prepared by contactingsorafenib free base with an acid of Formula HX.

The term “acid addition salt” as used in this application means a saltof an acid selected from the group containing hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid,1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid,trifluoroacetic acid, malic acid, tartaric acid, citric acid, lacticacid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoicacid, salicylic acid, phenylacetic acid and mandelic acid.

The term “contacting” may include dissolving, slurrying, stirring or acombination thereof.

The reaction of sorafenib free base with an acid of Formula HX may becarried out by directly contacting sorafenib free base with the acid ofFormula HX. The reaction may also be carried out in the presence of asuitable solvent. A solution of the acid of Formula HX in a suitablesolvent may also be used.

The suitable solvent may be selected from the group comprising of water,polar organic solvents, dipolar aprotic organic solvents and mixturesthereof.

Polar organic solvents may be selected from the group consisting oforganic solvents containing 1-5 carbon atoms and at least one hydroxylgroup, cyclic ethers, alkyl acetates and mixtures thereof. Examples oforganic solvents containing 1-5 carbon atoms and at least one hydroxylgroup are methanol, ethanol, n-propanol, isopropanol, n-butanol,sec-butanol, isobutanol, n-pentanol, glycerol or ethylene glycol.Examples of cyclic ethers are tetrahydrofuran or 1,4-dioxane. Examplesof alkyl acetates are methyl acetate, ethyl acetate, propyl acetate orbutyl acetate.

Dipolar aprotic organic solvents may be selected from the groupconsisting of ketones, amides, nitriles, sulphoxides or mixturesthereof. Examples of ketones are acetone, methyl ethyl ketone or methylisobutyl ketone. Examples of amides are N,N-dimethylformamide orN,N-dimethylacetamide. Examples of nitriles are acetonitrile orpropionitrile. Examples of sulphoxides are dimethyl sulfoxide or diethylsulphoxide.

In the preferred embodiments of the present invention, the reaction ofsorafenib free base with an acid of Formula HX may be carried out inpolar organic solvents selected from organic solvents containing 1-5carbon atoms and at least one hydroxyl group, such as methanol, ethanol,n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol,glycerol or ethylene glycol.

In some other preferred embodiments of the present invention, thereaction of sorafenib free base with an acid of Formula HX may becarried out by directly contacting sorafenib free base with acid ofFormula HX.

The reaction of sorafenib free base with an acid of Formula HX may becarried out at a temperature of about −5° C. to about 100° C.

In one embodiment, the reaction of sorafenib free base with an acid ofFormula HX may be carried out at about 0° C. In another embodiment, thereaction of sorafenib free base with an acid of Formula HX may becarried out at about 25° C. to about 35° C. In yet another embodiment,the reaction of sorafenib free base with an acid of Formula HX may becarried out at about 50° C. to about 80° C.

The reaction of sorafenib free base with an acid of Formula HX may becarried out for a period of about 10 minutes to about 8 hours,preferably for about 15 minutes to about 6 hours.

An anti-solvent may be added to the reaction mixture. The anti-solventmay be selected from the group consisting of hydrocarbons, ethers,chlorinated hydrocarbons and mixtures thereof. Examples of hydrocarbonsare hexane, cyclohexane, benzene, toluene, heptane or octane. Examplesof ethers are diethyl ether, methyl tert-butyl ether or diisopropylether. Examples of chlorinated hydrocarbons are chloroform,dichloromethane or 1,2-dichloroethane, water.

In the preferred embodiments of the present invention, the anti-solventmay be selected from the group comprising of ethers such as diethylether, methyl tert-butyl ether or diisopropyl ether.

The reaction mixture may be stirred for about 30 minutes to about 2hours, preferably for about 1 hour.

Water may be removed from the reaction mixture by forming an azeotropewith a suitable solvent. The suitable solvent may be selected fromhydrocarbons and mixtures thereof with chlorinated hydrocarbons, dipolaraprotic solvents and water. In the preferred embodiment of the presentinvention, water may be removed from the reaction mixture by forming anazeotrope with a hydrocarbon such as hexane, cyclohexane, benzene,toluene, heptane or octane.

Isolation may be accomplished by concentration, precipitation, cooling,filtration or centrifugation, or a combination thereof, followed bydrying.

The acid addition salts of Formula VII may be further purified bytrituration or crystallization in a suitable solvent. The suitablesolvent may be selected from hydrocarbons, alkyl acetates or mixturesthereof.

In a preferred embodiment of the present invention, the acid additionsalts of Formula VII may be purified by trituration in a hydrocarbonsolvent such as hexane, cyclohexane, benzene, toluene, heptane oroctane.

The processes of the present invention provide acid addition salts ofsorafenib of Formula VII having high purity.

Solvates and hydrates of acid addition salts of Formula VII are alsoincluded within the scope of the present invention.

The acid addition salts of Formula VII may be conventionally formulatedinto tablets, capsules, suspensions, dispersions, injectables and otherpharmaceutical forms. Any suitable route of administration may beemployed for example peroral or parental.

The acid addition salts of sorafenib may be further used for preparationof sorafenib of Formula I of high purity by contacting with a base. Thebase may be selected from group comprising of hydroxides, carbonates andbicarbonates of alkali and alkaline earth metals, ammonia, alkyl amines,hydrazine and the like. Examples of hydroxides, carbonates andbicarbonates of alkali and alkaline earth metals may include lithiumhydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium bicarbonate or potassium bicarbonate.Examples of alkyl amines may include diethyl amine, triethyl amine ormethyl diethyl amine.

The processes of the present invention provide sorafenib free base ofhigh purity.

In the foregoing section, embodiments are described by way of examplesto illustrate the process of invention. However, this is not intended inany way to limit the scope of the present invention. Several variants ofthe examples would be evident to persons ordinarily skilled in the artwhich are within the scope of the present invention.

Methods

XRD

Instrument: Panalytical

Mode: Expert PRO

Detector: Xcelerator

ScanRange: 3-40

Step size: 0.02

Range: 3-40° 2θ

DSC Mettler Toledo (DSC 821e)

TGA TA instruments (Q 500)

EXAMPLES Example 1 Preparation of Sorafenib Hydrochloride

Methanol (5 mL) was added to a reaction vessel containing sorafenib freebase (1.0 g) and the reaction mixture was stirred for about 5 minutes.Methanolic HCl (5 mL) was added gradually to the above reaction mixtureat 0° C. The reaction mixture was stirred for about 1 hour. Diisopropylether (10 mL) was added. The reaction mixture was stirred for about 1hour. The solid was filtered and dried under reduced pressure at about50° C. for about 3 hours to obtain sorafenib hydrochloride.

Yield: 74.7%

Example 2 Preparation of Sorafenib Hydrochloride

Methanol (35 mL) was added to a reaction vessel containing sorafenibfree base (7.0 g) and the reaction mixture was stirred for about 5minutes. Methanolic HCl (35 mL) was added drop wise to the abovereaction mixture at 0° C. The reaction mixture was stirred for about 1hour. Diisopropyl ether (70 mL) was added. The reaction mixture wasstirred for about 1 hour. The solid was filtered and dried under reducedpressure at about 50° C. for about 3 hours. The solid was trituratedwith toluene (20 mL) and reaction mixture was concentrated. The solidwas washed with toluene (2×20 mL), dried under reduced pressure at about30° C. for about 24 hours to obtain sorafenib hydrochloride.

Yield: 55%

Example 3 Preparation of Sorafenib Hydrobromide

Aqueous hydrogen bromide (15 mL) was added to a reaction vesselcontaining sorafenib free base (3.0 g) and the reaction mixture wasstirred for about 5 minutes. Temperature was raised to about 70° C. Thereaction mixture was stirred for about 2 hours. Solid precipitated out.The reaction mixture was concentrated and purified by adding toluene(3×15 mL) and concentrated to obtain a solid. Ethanol (2 mL) was added.The reaction mixture was stirred for about 5 minutes followed byaddition of diisopropyl ether (5 mL). The solid was filtered and driedat about 50° C. for about 12 hours to obtain sorafenib hydrobromide.

Yield: 73.8%

Example 4 Preparation of Sorafenib Methane Sulphonate

Ethanol (10 mL) was added to a reaction vessel containing sorafenib freebase (4 g). The reaction mixture was stirred for about 5 minutes.Methane sulphonic acid (0.55 mL) was added drop wise. The reactionmixture was stirred for about 4-5 hours. The solid was filtered, washedwith ethanol (2×10 mL) and dried under reduced pressure at about 50° C.for about 12 hours to obtain sorafenib methane sulphonate.

Yield: 66%

Example 5 Preparation of Sorafenib Sulphate

Ethanol (25 mL) was added to a reaction vessel containing sorafenib freebase (5 g). The reaction mixture was stirred for about 5 minutes.Temperature was raised to about 60° C. The reaction mixture was stirredfor about 30 minutes. Sulphuric acid solution (sulphuric acid: ethanol:water: 0.57 mL: 6 mL: 19 mL) was added drop wise. The reaction mixturewas cooled to room temperature and stirred for about 12 hours. Thereaction mixture was concentrated. The solid was filtered and driedunder reduced pressure at about 50° C. for about 12 hours to obtainsorafenib sulphate.

Yield: 89%

1. Crystalline sorafenib hydrochloride of Formula III

characterized by X-ray diffraction peaks having d-spacing values atabout 3.69, 3.63, 3.42, 3.39 and 3.05 Å.
 2. Crystalline sorafenibhydrochloride of claim 1 further characterized by X-ray diffractionpeaks having d-spacing values at about 6.40, 4.22, 4.06 and 3.60 Å. 3.Crystalline sorafenib hydrochloride of claim 1 characterized by DSCthermogram having endotherms at about 68[0.33]° C., 115[0.21]° C. and152[0.74]° C.
 4. Crystalline sorafenib hydrochloride of claim 1characterized by X-ray diffraction spectrum, DSC thermogram, TGA and IRspectrum as depicted in FIGS. 1, 2, 3 and 4, respectively. 5.Crystalline sorafenib hydrobromide of Formula IV

characterized by X-ray diffraction peaks having d-spacing values atabout 4.74, 4.66, 3.67, 3.61 and 3.39 Å.
 6. Crystalline sorafenibhydrobromide of Formula IV of claim 5 further characterized by X-raydiffraction peaks having d-spacing values at about 5.28, 4.17, 3.73,3.72 and 3.45 Å.
 7. Crystalline sorafenib hydrobromide of Formula IV ofclaim 5 characterized by DSC thermogram having endotherm at about262[0.27]° C.
 8. Crystalline sorafenib hydrobromide of Formula IV ofclaim 5 characterized by X-ray diffraction spectrum, DSC thermogram, TGAand IR spectrum as depicted in FIGS. 5, 6, 7 and 8, respectively. 9.Crystalline sorafenib methane sulphonate of Formula V

characterized by X-ray diffraction peaks having d-spacing values atabout 5.41, 5.20, 4.14, 3.68 and 3.58 Å.
 10. Crystalline sorafenibmethane sulphonate of Formula V of claim 9 further characterized byX-ray diffraction peaks having d-spacing values at about 10.80, 5.85,5.20, 4.58 and 4.41 Å.
 11. Crystalline sorafenib methane sulphonate ofFormula V of claim 9 characterized by DSC thermogram having endotherm atabout 205[0.07]° C.
 12. Crystalline sorafenib methane sulphonate ofFormula V of claim 9 characterized by X-ray diffraction spectrum, DSCthermogram, TGA and IR spectrum as depicted in FIGS. 9, 10, 11 and 12,respectively.
 13. Amorphous form of sorafenib sulphate of Formula VI


14. Amorphous sorafenib sulphate of Formula VI characterized by X-raydiffraction spectrum, DSC thermogram, TGA and IR spectrum as depicted inFIGS. 13, 14, 15 and 16, respectively.
 15. A process for the preparationof acid addition salts of sorafenib of Formula VII

wherein HX is an acid selected from hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulphonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid,1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid,trifluoroacetic acid, malic acid, tartaric acid, citric acid, lacticacid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoicacid, salicylic acid, phenylacetic acid or mandelic acid comprisingcontacting sorafenib free base of Formula I

with an acid of Formula HX.
 16. The process according to claim 15,wherein sorafenib free base is obtained as a solution directly from areaction in which sorafenib is formed and is used as such withoutisolation.
 17. The process according to claim 15, wherein the reactionis carried out by directly contacting sorafenib free base with the acidof Formula HX.
 18. The process according to claim 15, wherein thereaction is carried out in the presence of a suitable solvent selectedfrom the group comprising of water, polar organic solvents, dipolaraprotic organic solvents or mixtures thereof
 19. The process accordingto claim 15, wherein the reaction is carried out in polar organicsolvents selected from organic solvents containing at least one hydroxylgroup such as methanol, ethanol, n-propanol, isopropanol, n-butanol,sec-butanol, isobutanol, n-pentanol, glycerol or ethylene glycol. 20.The process according to claim 15, wherein the reaction is carried outat a temperature of about −5° C. to about 100° C.
 21. The processaccording to claim 15, wherein sorafenib acid addition salts of FormulaVII are purified by triturating or crystallizing in a suitable solventselected from hydrocarbons, alkyl acetates or mixtures thereof.
 22. Theprocess according to claim 21, wherein the hydrocarbon solvent isselected from hexane, cyclohexane, benzene, toluene, heptane or octane.23. Pharmaceutical composition(s) comprising sorafenib acid additionsalt(s) selected from crystalline sorafenib hydrochloride of FormulaIII, crystalline sorafenib hydrobromide of Formula IV, crystallinesorafenib methane sulphonate of Formula V or amorphous sorafenibsulphate of Formula VI and one or more pharmaceutically acceptablecarriers, diluents or excipients.
 24. Use of sorafenib acid additionsalts selected from crystalline sorafenib hydrochloride of Formula III,crystalline sorafenib hydrobromide of Formula IV, crystalline sorafenibmethane sulphonate of Formula V or amorphous sorafenib sulphate ofFormula VI for the treatment of cancer.